As one means of studying CNS-immune system interactions, our goal continues to be the elaboration and mediation of behaviorally conditioned alterations in immunologic reactivity. We will investigate the possibility of conditioning an enhancement of natural killer (NK) cell and immune responses, the conditions under which one observes conditioned suppression or enhancement of immune responses, and the extent to which these depend upon conditioned behavioral responses. Thus, conditioned changes in NK cell activity will be studied using interferon-inducers (e.g. Poly I:C and morphine as a unconditioned stimuli (UCSs) in multiple-trial conditioning paradigms that will enable the detection of possible conditioned compensatory responses. In the case off morphine, conditioned changes in NK activity will be related to behavioral responses in a taste aversion situation and in a learning paradigm in which morphine has positively reinforcing effects. Conditioning studies that do not involve immunomodulating drugs will also be undertaken. In one instance, the decreased antibody response to an antigenic stimulus administered after repeated exposures to ip injections of saline will be examined as a conditioning phenomenon . Particular emphasis will be directed to enhanced antibody responses to an immunologically neutral (conditioned) stimulus previously paired with an antigen (the UCS). Distinctively flavored drinking solutions will serve as conditioned stimuli (CSs) and antigens (e.g., keyhole limpet hemacyanin, KLH) will serve as UCSs. Conditioned C3H/Hej mice would receive multiple CS-UCS pairings at intervals of 3 weeks. On the test day, one group would be reexposed to the CS and one group would not. These groups will be further subdivided into those that are and those that are not given a low- dose ("booster") injection of KLH on the test day. Nonconditioned and Placebo-treated control groups would be similarly manipulated. We will establish the generality of conditioned antibody responses by using different antigens as UCS and, in a series of studies, assess the specificity of the conditioned response (i.e., determine if the conditioned changes responsible for the enhanced production of antibody are a consequence of immunologic reactions specific to the antigen used as the UCS or are mediated by nonspecific immunologic or neuroendocrine reactions induced by exposure to antigenic stimuli). In pursuing the mediating mechanisms, the effects of conditioning on B and T cell functions and on cytokines (interleukin-1 and -2), and on norepinephrine changes in spleen and in specific regions of the hypothalamus will be examined. The proposed research will increase our understanding of the means by which behavior can serve an immunoregulatory function and provide an experimental foundation for and new approaches to the study of adaptive processes in health and in a variety of disease processes such as autoimmune diseases, infectious diseases, and AIDS which involve disordered regulation of the immune system.